2-haloandrost-1-ene-3, 17-diones



United States 2,980,710 v Z-HALOANDROST-1-ENE 3,17-DINES Raymond E.Counsel! and Paul D. Klimstra, Skokie, lll., .assignors to G. D.'Searle& Co., -Chicago, 111., a corporation of Delaware No Drawing. Filed July1, 1960, Ser. No. 40,194

'4 *Claims. (Cl. 260-3973) I The present invention is concerned with2-halogenated steroids and, more particularly, with 2-halo derivativesof Sea-androstd-ene-3,l7-dione as represented by the structural formulawherein X is a halogen atom of atomic Weight less than 100.

atent 0 The halogen atoms encompassed by- X are fluorine,

chlorine and bromine. v V

The 2-bromo and 2-chloro compounds of this invention are convenientlyprepared by reaction of la,2a-epoxy- 2,980,710 Patented Apr. 18, 1961departing from the spirit of the invention. The temperaturesdisclosed inthese examples are given in degrees centigrade C.), and quantities ofmaterials are given in parts by weight unless otherwise noted.

Example 1 about 255 millimicrons with a molecular extinctioncoefiicientof about 7600. I I i i 2 Example 2 v A solution of one partof 1u,2a-epoXy-Sa-androstane- 3,17-dione in 32 parts of acetone and 1'0parts of dioxane is treated with 3 parts of concentrated hydrochloricacid,

and the resulting solution is allowed to stand at room temperature forabout one hour, then diluted with a mixture of ice and aqueous sodiumchloride. The solid product which precipitateslis collected on a filter,washed thereon with water, and recrystallized from aqueousethanol toproduce pure Z-ChlOIO-Sot-Ztl'ldIOSt-1-6I16-3,17-di0n6, M.P. l46l48;'[a]=|-117- (chloroform). It displays a maximum in the ultraviolet atabout247 millimicrons with a molecular extinction coefiicient of about 9100.

5a-androstan-3,l7-.dione "with the appropriate hydrogen halide in apolar solvent medium. Typically, this epoxide in acetone is allowed toreact with hydrobromic acid at room temperature for about one hour toproduce 2-bromo- 5aandros-t-l-ene-3,17-dioneL A particularly suit-ableprocess for the manufacture of the Z-fluorocompound of this inventionutilizes as the starting material, 3 ,8-( p-toluenesulfonyloxy) -5a-androstan- 17-one. A solution of this ester in collidine is heated atthe reflux temperature of the mixture to alford Su-androst- 2-en-l7-one.perbenzoic acid in benzene, to atford 2a,3a-epoxy-5u-' androstan 17-one.Treatment of this epoxide with anhydrous hydrogen fluoride in achloroform-tetrahydrofuran solution results in 2,8-fluoro-3a-hydroxy-5aandrostan-l7-one. Oxidation of this 3a-hydroxy compound, suitably inacetone with aqueous chromic acid, yields 2fifluoro-5a-androstane-3,17-dione, which is epimerized by treatment inacetic acid with hydrobromic acid to yield2a-fiuoro-5u-androstane-3,l7-dione. the latter substance in'glacialacetic acid containing a catalytic quantity of hydrobromic acid istreated with, bromine to aiford 2fi-bromo-2a-fluoro-5a-androstane3,17-dione, which is dehydrobrominated by means of a solution of lithiumchloride and lithium carbonate in dimethylformamide, resulting in theinstant 2- fiuoro-5a- I androst-1-ene-3,17-dione.

The compounds of this invention exhibit valuable v pharmacologicalproperties. They possess, for example, hormonal activity as evidenced bytheir ability to evoke This olefin is epoxidized, typically with' Asolution of stirred and heated at reflux for about 4 hours.

reaction mixture is cooled, then treated with ice and' Example 3 Amixture of 5 parts of 3B-(p-toluenesulfonyloxy)-50;- andros tan-17-oneand 350 parts of purified collidineis This 500 parts by volume of 1 Nsulfuric acid. The resulting mixture is extracted with ether, and theorganic layer is washed successively with ice-cold l N sulfuric acid,aqueous sodium bicarbonate, and Water. This washed solution is dried anddecolorized over a mixture of an- ,hydrous sodium sulfate and activatedcarbon, then evappure sample, M.P. l05106.5; [wh 163' (chloroand 34parts of purified tetrahydrofuran, cooled by means.

of 'an ice-calcium chloride bath, is bubbled 20.8 parts stirred mixtureis added a solution of 12 parts of 2a,3aepOxy-Stx-androstan-d7-one' in96 parts of chloroform,

- over aperiodiof about 2 /2 hours, during which time the addition ofhydrogen fluoride is continued. The cooling bath is' then removed andthe reaction mixture is' stirred those skilled in the art that theseexamples can be modi- I fled in regard toboth materials and methodswithout orated to dryness to afiord 5a-ar'rdrost-2-en-l7-one, M.P.103-105. Recrystallization from methanol affordsa form).-

Example: 4 To a solution of 8.4 parts of perbenzoic acid in 128 parts ofbenzene, cooled at 5, is added 15 parts'of 50tandrost-2-en-17-one, andthe mixture is stirred until lization from methanol affords pure2a,3a-6p0Xy5oL-' androstan-l7-one, M.P. about 123-126"; [u] =+104(chloroform). .7 t

I Example Into a solution c'onsistingof 21 parts of chloroform ofanhydrous hydrogen fluoride. To this cooled and .for about 1 /2 hourslonger, then,,..poured slowly irito This substance exhibits anultraviolet absorption maxirnurrr a-t about 1050 parts of concentratedaqueous potassium carbonate. This mixture is extracted with chloroform,

and the organic extract is washed successively with water,

Example 6 -A rapidly-stirred solution of 4 parts of2fi-fluoro-3ahydroXy-Sa-androstan-17-one in 40 parts of acetone iscooled and treated dropwise with an aqueous solution,

8 N in chromium trioxide and 8 N in sulfuric-acid, until precipitationof the green-colored salts ceases. Dilution of the reaction mixture withice and water results in formation of an oil, which is separated byextraction into methylene chloride; This organic solution is then washedwith water, dried over anhydrous potassium carbonate, and concentratedin vacuo to yield an oil, which solidifies period of about one hour, 0.8part of bromine. This reactionmixture is poured slowly intoice andwater, and the On standing. Recrystallization from aqueous methanolaffords pure 2fl-fluoro-5a-androstane-3,l7-dione, M.P.

142143; [a] =+f12 (chloroform).

' Example 7 A stirred solution of 3 parts of 2B-fluoro-5a-androstane-3,17-dione in 75 parts of glacial acetic acid is treated with 17.8 partsof 48% hydrobromic acid, and the resulting mixture is stored at roomtemperature for about To a solution of 1.5 parts of2ot-fiuoro-5a-androstaue- '3,17-dione and 0.15 part of 48% hydrobromicacid in v parts of glacial acetic acidis added dropwise over a resultingprecipitate is collected by filtration, washed successively with aqueoussodium bicarbonate and water, then dried to afford a solid, whichcontains 2fl-bromo- 2a-fluoro-5a-androstane-3,17-dione.

To a solution of this dried precipitate in "10 parts ofdimethylformamide is added 0.45 part of lithium chloride and 0.27part'of lithium carbonate, and the resulting mixture is heated atreflux, under nitrogen, for about 4 /2 hours. water. Extraction of thismixture with ether afiords an organic solution, which iswashedsuccessively with aqueous sodium bicarbonate and water, then dried overanhydrous potassium carbonate. Distillation of the solvent in vacuoaffords a glass-like residue which is adsorbed on a silica gelchromatographic column and eluted with 5% ethyl acetate in benzene.Concentration of the eluate followed by recrystallization of theresulting residue from acetone-hexane affords'needle-like crystals of2-fluoro-5e-androst-1-ene-3,l7dione, M.P." about 188 190"; [a] =+l22(chloroform).

What is claimed is:

1. A compound of the structural formula H30 0 ll wherein X is a halogenatom of atomic weight less than 100. a

2. 2-bromo-5a-androst-1-ene-3,17-dione.

3. 2-chloro-5a-androstd-ene-3,17-dione.

4. 2-fluoro-5u-androst-l-ene-3,17-dione.

No references cited.

It is then cooled and poured slowly into

1. A COMPOUND OF THE STRUCTURAL FORMULA 